SOD and inhaled nitric oxide normalize phosphodiesterase 5 expression and activity in neonatal lambs with persistent pulmonary hypertension
SOD and inhaled nitric oxide normalize phosphodiesterase 5 expression and activity in neonatal lambs with persistent pulmonary hypertension
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DOI：
10.1152/ajplung.00309.2009
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发表时间：
2010-07-01
影响因子：
4.9
通讯作者：
Steinhorn, Robin H.
中科院分区：
文献类型：
--
作者：
Farrow, Kathryn N.;Lakshminrusimha, Satyan;Steinhorn, Robin H.
首页--期刊主要分类--期刊细介绍--期刊题录与文摘--期刊详细文摘内容超氧化物歧化酶和吸入一氧化氮可使持续性肺动脉高压新生羔羊的磷酸二酯酶5的表达和活性正常化。Am J Physiol肺细胞Mol Physiol 299：L109-L116,2010。首次发表于2010年4月16日；doi:10.1152/ajplung.00309.2009.-Phosphodiesterase 5(PDE5)和可溶性鸟苷环化酶(SGC)是cGMP和肺血管张力的关键调节因子。在绵羊持续肺动脉高压(PPHN)的绵羊导管结扎模型上，我们研究了氧气加或不加吸入一氧化氮(INO)或重组人铜锌超氧化物歧化酶(Rh SOD)对sGC、PDE5和cGMP的影响。PPHN羔羊单独吸入100%O2 24 h，或联合吸入20ppm(Ppm)iNO或气管内单次吸入rhSOD(5 mg/kg)。将通风的PPHN羔羊与PPHN胎儿、对照胎儿和1日龄自然呼吸羔羊(1DSB)进行比较。在1DSB羔羊的小动脉中，sGC表达增加，PDE5表达减少，cGMP浓度升高。在呼吸100%O-2的PPHN羔羊中，sGC活性增加到与1DSB水平相当的水平。然而，PDE5的表达和活性增加，cGMP水平保持在胎儿水平。添加iNO或rhSOD均可降低PPHN羔羊PDE5的表达和活性，并使cGMP水平升高至与1DSB羔羊相当的水平。这些数据表明，PPHN羔羊在100%氧气中通气会损害cGMP介导的血管扩张，部分原因是PDE5的表达和活性增加。加入iNO或rhSOD均可使PDE5和cGMP水平正常化。因此，旨在减少PDE5和增加cGMP的疗法，如iNO和rhSOD，可能被证明在治疗新生儿PPHN方面是有效的。
Farrow KN, Lakshminrusimha S, Czech L, Groh BS, Gugino SF, Davis JM, Russell JA, Steinhorn RH. SOD and inhaled nitric oxide normalize phosphodiesterase 5 expression and activity in neonatal lambs with persistent pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 299: L109-L116, 2010. First published April 16, 2010; doi:10.1152/ajplung.00309.2009.-Phosphodiesterase 5 (PDE5) and soluble guanylate cyclase (sGC) are key regulators of cGMP and pulmonary vascular tone. We sought to determine the impact of mechanical ventilation with O-2 with or without inhaled nitric oxide (iNO) or recombinant human Cu/Zn SOD (rhSOD) on sGC, PDE5, and cGMP in the ovine ductal ligation model of persistent pulmonary hypertension of the newborn (PPHN). PPHN lambs were ventilated with 100% O-2 for 24 h alone or combined with either inhalation of 20 parts per million (ppm) iNO continuously or a single intratracheal dose of rhSOD (5 mg/kg). Ventilated PPHN lambs were compared with PPHN fetuses, control fetuses, and 1-day-old spontaneously breathing lambs (1DSB). In the small pulmonary arteries of 1DSB lambs, sGC expression increased, PDE5 expression decreased, and cGMP concentrations increased relative to fetal levels. In PPHN lambs ventilated with 100% O-2, sGC activity increased to levels comparable with 1DSB levels. However, PDE5 expression and activity increased, and cGMP levels remained at fetal levels. Addition of either iNO or rhSOD decreased PDE5 expression and activity in PPHN lambs and increased cGMP levels to levels comparable with 1DSB lambs. These data suggest that ventilation of PPHN lambs with 100% O-2 impairs cGMP-mediated vasodilation in part due to increased PDE5 expression and activity. The addition of either iNO or rhSOD normalized PDE5 and cGMP levels. Thus therapies designed to decrease PDE5 and increase cGMP, such as iNO and rhSOD, may prove useful in the treatment of PPHN in newborn infants.